Diacylglycerol O-acyltransferase, also known as diglyceride acyltransferase or (DGAT), is found in the microsomal fraction of cells. DGAT plays an essential role in the metabolism of cellular diacylglycerol and is critically important for triglyceride production and energy storage homeostasis (Eu. J. Biochem. 1989, 182, 395-400). DGAT catalyses the final and rate limiting step in the triacylglycerol synthesis from 1,2-diacylglycerol (DAG) and long chain fatty acyl CoA as substrates (Lipid Res., 1996, 35, 169-201). Although triglycerides are essential for normal physiology, excess triglyceride accumulation results in obesity and, particularly when it occurs in non adipose tissues, is associated with insulin resistance.
Two DGAT genes (DGAT 1 and DGAT 2) have been cloned and characterized. Both the encoded proteins share no sequence homology but they catalyze the same reaction (Proc. Natl. Acad. Sci. USA, 1998, 95, 13018-13023; J. Biol. Chem., 2001, 276, 38870-38876). The enzymes are widely expressed; however some differences do exist in the relative abundance of expression in various tissues.
Studies in the gene knockout mice have indicated that pharmacological inhibition of DGAT1 would be of value in the treatment of Type II diabetes and obesity. DGAT1 knockout (DGAT1−/−) mice are viable and capable of synthesizing triglycerides, as evidenced by normal fasting serum triglyceride levels and normal adipose tissue composition. DGAT1−/− mice have less adipose tissue than wild type mice at baseline and are resistant to diet induced obesity. Metabolic rate is ˜20% higher in DGAT1−/− mice than in wild type mice on both regular and high fat diets (Nature Genetics, 2000, 25, 87-90). Increased physical activity in DGAT1−/− mice partially accounts for their increased energy expenditure. DGAT1−/− mice also exhibit increased insulin sensitivity. Thus phenotype of DGAT1 knock out mice suggests that DGAT1 inhibitors have utility for the treatment of obesity and associated complications like Type II diabetes and metabolic syndrome.
DGAT enzymes produce the fat that is stored in the droplets—important for HCV replication. DGAT1 interacts with one viral protein, the viral nucleocapsid core protein, required for viral particle assembly. The core protein normally associates with the surface of fat droplets but cannot do so when. DGAT1 is inhibited or missing in infected cells. Hence, HCV infection and viral particle production are severely impaired in liver cells that lack DGAT1 activity (Nature Medicine, 2010, 16, 1295-1298).
Several patent applications and publications describe the discovery of small molecule DGAT1 inhibitors (dibenzoxazepinones EP 1219716; substituted amino-pyrimidino oxazines, WO2004047755, amide compounds, WO2008011131; piperidine/piperazine derivatives, WO2008148840; pyrazine carboxamides, WO2010146395; oxadiazole and oxazole substituted benzimidazole and indole derivatives, WO2009040410; amino-dihydropyrido-pyrimidinone compounds, oxazole compounds, WO2010059602; US20100197590; substituted bicyclolactam compounds, WO2009016462; Imidazole derivatives, WO2012047772; WO2012009217, Spirocyclic compounds; Inhibitors of diacylglycerol acyltransferase: a review of 2008 patents, Expert Opin. Ther. Patents, 2010, 20(1), 19-29; J. Med. Chem. 2009, 52, 1558-1568; J. Med. Chem. 2008, 51, 380-383; J. Med. Chem., 2011, 54 (7), 2433-2446; ACS Med. Chem. Lett., 2011, 2 (5), 407-412; ACS Med. Chem. Lett., 2012, 3 (5), 411-415; Bioorg. Med. Chem. Lett., 2012, 22, 3873-3878. WO2006064189 describes oxadiazole compounds as DGAT1 inhibitors. However, only few small molecule DGAT1 inhibitors are in clinical trials. For example, LCQ-908 from Novartis is in Phase 2 clinical trials for the treatment of HCV, hypertriglyceridemia and T2D. Pfizer and AstraZeneca have recently discontinued their DGAT1 inhibitors from Phase 1 clinical trials. No DGAT1 inhibitor has yet reached the marketing stage. Therefore, there remains a need for discovering novel DGAT1 inhibitors possessing desirable properties such as pharmacokinetic/dynamic and or physicochemical and/or other drug like profiles to advance into clinics.